ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive memory loss and cognitive decline. Histopathologically, brains of AD patients exhibit an accumulation of amyloid plaques, formed of amyloid ? (A?) peptides, and of neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. In the early stages of the disease, enhanced depolarization- stimulated release of glutamate (Glu) and accumulation of A? and aberrant tau triggers Glu-induced, NMDA receptor (NMDAR)-dependent excitotoxicity that leads to impaired cognition and eventual neuronal loss. Recent work has revealed that the benzothiazole riluzole prevents age-related cognitive decline in rats and in transgenic mouse models of AD that express mutant human tau or production of toxic A? peptides. Riluzole is thought to exert its effects, in part, by reducing activity-stimulated synaptic Glu release. The use of riluzole as a therapeutic agent to limit Glu-induced NMDAR excitotoxicity, however, is limited because riluzole is not very brain penetrant, interacts with multiple pharmacologic targets and causes sedation at higher doses. Excessive and sustained Glu release from synapses triggers NMDA-dependent excitotoxicity in many acute and chronic neurodegenerative conditions. Glu release from synapses must be rapidly recycled to maintain the presynaptic Glu supply for excitatory neurotransmission under high neuronal activity. Glutamine (Gln) released from glia is thought to serve as a precursor for Glu in synaptic terminals under these conditions. We have discovered that neural activity stimulates Gln transport in neurons and that such activity-stimulated Gln transport is coordinately regulated with synaptic Glu release. Interestingly, activity-stimulated Gln transport in pyramidal neurons is one of the most potently inhibited targets of riluzole (IC50 = 1M). We have developed novel riluzole- derived compounds that are potent inhibitors of activity-stimulated Gln transport and are neuroprotective for this project. Importantly, these compounds are up to 7X more brain penetrant than riluzole, 15X more potent against activity-stimulated Gln transport than other targets of riluzole (e.g., Na+ channel blockade) and therefore are more selective, with potentially fewer side effects. The overall goals of the studies proposed are to 1) test the hypothesis that novel riluzole-derivatives preferentially block activity-stimulated Gln transport and activity-regulated Glu release in mouse hippocampal synapses are more brain penetrant and have longer half- lives than riluzole and 2) test the hypothesis that novel riluzole-derivatives that preferentially block activity- stimulated Gln transport in synapses reduce A? load in the entorhinal cortex and hippocampus and attenuate cognitive impairment in a transgenic early-onset AD model (5xFAD mice). Riluzole derivatives that selectively block activity-stimulated Gln transport and reduce Glu-induced/NMDAR-dependent excitotoxicity in hippocampal synapses offer a presynaptic, more brain penetrant and selective therapeutic approach to AD and other related dementias that will complement existing FDA-approved medications (e.g., memantine).